20 ms·

Yeah, but thats hardly news, we have known that for decades. Otherwise direct serotonin releasers would be the most useful ADs. But these mostly give people nau

Yeah, but thats hardly news, we have known that for decades. Otherwise direct serotonin releasers would be the most useful ADs. But these mostly give people nausea and serotonin syndrome. ADs work mostly by being FIASMAs, reducing inflammation and oxidative stress, increasing neurogenesis and neuroplasticity, increasing the activity of other monoaminergic systems, and the serotonergic portion is mostly explained by downregulation of 5-HT1A autoreceptors due to chronicly high extrasynaptic 5-HT levels. This also explains the delayed action of ADs. At least this is my knowledge from when I last researched this topic in depth. But that would be a little bit too much for the general public, so it is simplified, to this annoying effect that everyone talks of "low serotonin levels" where in fact the underlying systems are way more complex.

ZeroGravitas 4y ago
And now the opposite happens with headlines that imply "your medication is suddenly revealed to be useless" when in fact we've been aware that we don't know how it works for a while, but we're still reasonably sure it helps, which perhaps explains the increase in prescription more than the "serotonin is the only thing that matters" theory which the experts ruled out a while ago.
- virtuallynathan 4y ago
  They barely work better than placebo, from what I saw in my reading of the literature.
  - bratsche 4y ago
    I’ve tried a number of antidepressant drugs and so far not been able to notice much difference with any of them.
  - slibhb 4y ago
    Well, placebos work fairly well for depression. And it's not like doctors can prescribe them...
    - CharlesW 4y ago
      The AMA says they can if the patient is informed of and agrees to their use. But wouldn't that significantly impact their effectiveness?
    - jack_pp 4y ago
      So the solution is prescribing something that has a lot of unpleasant side-effects for a lot of people? Medication that if you don't take will have SEVERE withdrawal symptoms?
      - wins32767 4y ago
        I suddenly became allergic to SSRIs and had to go off of them cold turkey. I didn't have any withdrawal problems at all so it's not a universal issue.
        niemal_dev 4y ago
        Wow, just wow. Quitting them cold turkey 0 problems, incredible.
        wins32767 4y ago
        I'm not trying to minimize the problems other people have had with withdrawal at all, just saying that it's possible to have a variety of different outcomes being on and off of them.
      - slibhb 4y ago
        SSRIs have mild side effects after the first few weeks. Withdrawal varies but is generally manageable if you taper slowly. I'm open to alternatives but I'm convinced that antidepressants help people.
      - zasdffaa 4y ago
        I wonder why you say 'SEVERE' so severely. It doesn't sound like you have any direct experience of this. I had to come off them and it wasn't a problem. My biggest fear, and it was huge, was that the depression would return. It didn't.
  - swamp40 4y ago
    They work fantastically, from what I have seen firsthand many many times. There is a very good reason for it's use in up to 20% of the population in some groups in the US. Just because we haven't pinpointed why doesn't matter a bit.
    - bowsamic 4y ago
      Who should I trust? Peer reviewed literature, or one swampy boi?
    - dimal 4y ago
      “They work fantastically” is a statement that requires many qualifiers. They work fantastically for some subset of people. For other people, they do nothing. For other people, they have negative side effects that make them not worth whatever benefits they provide. For some people, they cause extreme negative effects when the medication is removed. For some other people, they increase the chance that they will commit suicide. It does matter that we haven’t pinpointed why they work for some people, because if we did, we might be able to avoid those negative effects and wasted time for the people for which they don’t work.
      - marcosdumay 4y ago
        If the effect is systematic, real, and measurable, it's just a matter of giving the medication to the people that benefit from it, and not giving it to the people that don't. The real question is by what level is the effect is systematic, real, and measurable?
  - NickM 4y ago
    There is also evidence that they might only work better than a typical placebo because the side effects make them an "active placebo", triggering a stronger placebo response. i.e. if you take a pill that doesn't make you feel any different, you may wonder if it's working, but if you feel weird and have unpleasant side effects then you know it's doing something. This is particularly underappreciated in the research done on these drugs, because a double-blind study isn't actually double-blind if many of the participants can easily tell whether they're in the placebo group due to very noticeable side effects. It's been mentioned in other comments, but I really recommend the work of Irving Kirsch on this; he's a brilliant scientist and his book The Emperor's New Drugs is a real eye-opener.
Workaccount2 4y ago
Anytime I learn about bodily functions I become more and more aware of how shit it's engineering is. Works amazing, sure, but try and fix or debug anything? Good luck.
- _jal 4y ago
  Tractors don't know how to repair each other, either.
  - Dudeman112 4y ago
    To be fair, tractors don't go on about how smart they are
- hutzlibu 4y ago
  Erm, are you aware of any other machine, that is able for self repairing and self replicating in a complex and changing environment? I really would not call my body bad engineering, just because I do not understand how it works in detail. Rather the opposite, the more I learn, the more amazed I am, how awesome it all is. The complex interactions of chemical, electrical and physical components. (And who knows, maybe even quantum field elements.) I could not design anything remotely complex at all. Also, I debug and fix my body all the time, or rather, my body does this mostly in auto mode.
- rustybelt 4y ago
  Are you saying God likes to yeet buggy unmaintainable spaghetti code directly into production?
  - N1H1L 4y ago
    DNA is spaghetti code exemplified. We are carried around tons of dead viral DNA for example - what amounts to shipping code with older code commented out.
    - rustybelt 4y ago
moth-fuzz 4y ago
I have a friend that's convinced that her ADHD 'causes depression' because her brain does not produce 'enough dopamine'. I'm noticing more and more among my peers a mythology around brain chemicals that's about as accurate as the four humors but with a scientific-sounding veneer. All brain function (and thus all bodily function, because the brain is the whole person /s) can be traced back to the presence or absence of a nominal amount of certain chemicals. I wonder how the popular understanding of these processes will evolve as more and more is discovered and understood.
- jugg1es 4y ago
  This is like the right/left brain generalization that everyone seems to still believe in.
- kemiller 4y ago
  I think ADHD causes depression because you get constant negative feedback from (many) teachers & bosses.
  - hirvi74 4y ago
    It's true, and I alluded to this more in depth in a comment in this chain. Growing up in the semi-rural South East, USA, where kids didn't get diagnosed with ADHD. (Fun fact -- I had 5 boys who were my childhood friends that grew up with. We all lived within 3 miles of each other, and all of us have ADHD -- something in the water maybe?) I didn't know I had ADHD until I was in a dark dark place in my early 20s after 4 years of college (only took me 6 years lol). I swear I have some kind of CPTSD from growing up with it. I developed all kinds of healthy and unhealthy coping mechanisms and a lot of anger and negative self-talk that I struggle with still to this day. I mean, I was chewed up and spit out by the public education system, little league sports, other children's parents, my peers, and even my own parents from time to time. Constantly, day in and day out, being punished, ridiculed, and humiliated for something I could not control. I didn't want to be that way, and I still don't want to be that way, but I am what I am. I would not consider myself to be anything but average intelligence, maybe even below average, but if it weren't for sheer luck and a determination to prove everyone wrong, then I do not think I would have survived.
harborseal 4y ago
Yes, but people are still being told by their psychiatrists that depression is caused by low serotonin levels as if it were an objective fact. Seeing this happen made me lose a lot of trust in the medical profession. Is it like this for all illnesses or just mental ones?
- hirvi74 4y ago
  I was told by a psychiatrist that I respect that one day in the future we may look back on psychiatry of today like we look at blood-letting and lobotomies of the past.
- kerryoco 4y ago
  many illnesses are reproducible. you can give people viruses and they do indeed get sick. so i don't think you need to discount the entirety of medicine. afaik, there is no reproducible causality for depression; we can't induce it. we only measure it's correlations and have % confidence in hypotheses.
- kmmlng 4y ago
  I don't think it is an isolated incident. Once something has become "known" among the public and the medical profession, it seems quite difficult to update it. Another example is the dietary cholesterol issue. The human body is incredibly complex and we have quite limited tools to study it, so we are bound to arrive at wrong conclusions. That by itself is to be expected, but what does really worry me is this missing knowledge updating mechanism. It can take decades for quite a substantial update on what we thought we knew to trickle down from academia to practicing medical professionals. At this point, if you have any kind of scientific literacy, it might be a good idea to verify whatever your doctor claims.
  - alsetmusic 4y ago
    > It can take decades for quite a substantial update on what we thought we knew to trickle down from academia to practicing medical professionals. A recent ep of the Trickle Down podcast (premium offshoot of a show that studies conspiratorial thinking, Q Anon Anonymous), discussed how we learned to treat ulcers with antibiotics and then lost that information for something like fifty years. Changing the scientific understanding of their cause had a Greek doctor going to his country’s health ministry over and over and getting rejected despite results. I think you nailed it.
lighttower 4y ago
Can you point us to a source for the accepted real physiological effects of ADs that you shared above?
- nth_order 4y ago
  Sure - I should have given some sources in my original comment. The order of my list of purported mechanisms is also not really ordered by significance. I think generally, more and more mechanisms of AD efficacy are discovered, and it can seem that the more we know, the less we know. Additionally of course, there are like 15 different classes of ADs, with hundreds of different compounds in total. What we know for sure I think is that the serotonin and also the monoamine hypotheses of depression are highly oversimplified and even internally contradictory, and many more targets and way more general biochemical mechanisms in the brain must be involved in depression. But anyways, here are some pointers: - Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277931/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277931/) - Wikipedia: Biology of Depression (https://en.wikipedia.org/wiki/Biology_of_depression#Monoamines https://en.wikipedia.org/wiki/Biology_of_depression#Monoamin...) has some good sources - One source covering the 5-HT1A autoreceptor downregulation part in particular there is "Serotonin autoreceptor function and antidepressant drug action" (https://pubmed.ncbi.nlm.nih.gov/10890313/ https://pubmed.ncbi.nlm.nih.gov/10890313/) - This is also covered in "Mechanisms underlying the speed of onset of antidepressant response": https://link.springer.com/chapter/10.1007/978-3-0348-8344-3_4 https://link.springer.com/chapter/10.1007/978-3-0348-8344-3_... - I personally like the books "Antidepressants" by Leonard (that the previous paper is a chapter of) and "Anxiolytics" by Briley and Nutt. These discuss really a wealth of observed/purported mechanisms, also for example including the significance of late gene products. - Wikipedia: Pharmacology of antidepressants (https://en.wikipedia.org/wiki/Pharmacology_of_antidepressants https://en.wikipedia.org/wiki/Pharmacology_of_antidepressant...) has great sources, especially on the anti-inflammatory and immunomodulative pathways, and introducing HPA axis modulation as another possible pathway. - Here's something about the significance of common ADs being FIASMAs: https://www.semanticscholar.org/paper/High-activity-of-acid-sphingomyelinase-in-major-Kornhuber-Medlin/30ad3dc9ba2c57ba2648e8613bdcc1111bc8a85a https://www.semanticscholar.org/paper/High-activity-of-acid-... - also check out the related articles below for more interesting material. - ADs and neuroplasticity: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025168/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025168/ - ADs and neurogenesis (this is not clear-cut in its clinical significance, and many ordinary things like exercise can promote neurogenesis): https://www.sciencedirect.com/science/article/abs/pii/S0163725820300437 https://www.sciencedirect.com/science/article/abs/pii/S01637... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155214/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155214/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230505/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230505/
barbs 4y ago
How common is seretonin syndrome amongst people who take SSRIs? My understanding of seretonin syndrome is that it's a serious life-threatening condition that can occasionally occur when people take too much MDMA.

ZeroGravitas 4y ago

And now the opposite happens with headlines that imply "your medication is suddenly revealed to be useless" when in fact we've been aware that we don't know how it works for a while, but we're still reasonably sure it helps, which perhaps explains the increase in prescription more than the "serotonin is the only thing that matters" theory which the experts ruled out a while ago.

virtuallynathan 4y ago
They barely work better than placebo, from what I saw in my reading of the literature.
- bratsche 4y ago
  I’ve tried a number of antidepressant drugs and so far not been able to notice much difference with any of them.
- slibhb 4y ago
  Well, placebos work fairly well for depression. And it's not like doctors can prescribe them...
  - CharlesW 4y ago
    The AMA says they can if the patient is informed of and agrees to their use. But wouldn't that significantly impact their effectiveness?
  - jack_pp 4y ago
    So the solution is prescribing something that has a lot of unpleasant side-effects for a lot of people? Medication that if you don't take will have SEVERE withdrawal symptoms?
    - wins32767 4y ago
      I suddenly became allergic to SSRIs and had to go off of them cold turkey. I didn't have any withdrawal problems at all so it's not a universal issue.
      - niemal_dev 4y ago
        Wow, just wow. Quitting them cold turkey 0 problems, incredible.
        wins32767 4y ago
        I'm not trying to minimize the problems other people have had with withdrawal at all, just saying that it's possible to have a variety of different outcomes being on and off of them.
    - slibhb 4y ago
      SSRIs have mild side effects after the first few weeks. Withdrawal varies but is generally manageable if you taper slowly. I'm open to alternatives but I'm convinced that antidepressants help people.
    - zasdffaa 4y ago
      I wonder why you say 'SEVERE' so severely. It doesn't sound like you have any direct experience of this. I had to come off them and it wasn't a problem. My biggest fear, and it was huge, was that the depression would return. It didn't.
- swamp40 4y ago
  They work fantastically, from what I have seen firsthand many many times. There is a very good reason for it's use in up to 20% of the population in some groups in the US. Just because we haven't pinpointed why doesn't matter a bit.
  - bowsamic 4y ago
    Who should I trust? Peer reviewed literature, or one swampy boi?
  - dimal 4y ago
    “They work fantastically” is a statement that requires many qualifiers. They work fantastically for some subset of people. For other people, they do nothing. For other people, they have negative side effects that make them not worth whatever benefits they provide. For some people, they cause extreme negative effects when the medication is removed. For some other people, they increase the chance that they will commit suicide. It does matter that we haven’t pinpointed why they work for some people, because if we did, we might be able to avoid those negative effects and wasted time for the people for which they don’t work.
    - marcosdumay 4y ago
      If the effect is systematic, real, and measurable, it's just a matter of giving the medication to the people that benefit from it, and not giving it to the people that don't. The real question is by what level is the effect is systematic, real, and measurable?
- NickM 4y ago
  There is also evidence that they might only work better than a typical placebo because the side effects make them an "active placebo", triggering a stronger placebo response. i.e. if you take a pill that doesn't make you feel any different, you may wonder if it's working, but if you feel weird and have unpleasant side effects then you know it's doing something. This is particularly underappreciated in the research done on these drugs, because a double-blind study isn't actually double-blind if many of the participants can easily tell whether they're in the placebo group due to very noticeable side effects. It's been mentioned in other comments, but I really recommend the work of Irving Kirsch on this; he's a brilliant scientist and his book The Emperor's New Drugs is a real eye-opener.

Workaccount2 4y ago

Anytime I learn about bodily functions I become more and more aware of how shit it's engineering is. Works amazing, sure, but try and fix or debug anything? Good luck.

_jal 4y ago
Tractors don't know how to repair each other, either.
- Dudeman112 4y ago
  To be fair, tractors don't go on about how smart they are
hutzlibu 4y ago
Erm, are you aware of any other machine, that is able for self repairing and self replicating in a complex and changing environment? I really would not call my body bad engineering, just because I do not understand how it works in detail. Rather the opposite, the more I learn, the more amazed I am, how awesome it all is. The complex interactions of chemical, electrical and physical components. (And who knows, maybe even quantum field elements.) I could not design anything remotely complex at all. Also, I debug and fix my body all the time, or rather, my body does this mostly in auto mode.
rustybelt 4y ago
Are you saying God likes to yeet buggy unmaintainable spaghetti code directly into production?
- N1H1L 4y ago
  DNA is spaghetti code exemplified. We are carried around tons of dead viral DNA for example - what amounts to shipping code with older code commented out.
  - rustybelt 4y ago

moth-fuzz 4y ago

I have a friend that's convinced that her ADHD 'causes depression' because her brain does not produce 'enough dopamine'. I'm noticing more and more among my peers a mythology around brain chemicals that's about as accurate as the four humors but with a scientific-sounding veneer. All brain function (and thus all bodily function, because the brain is the whole person /s) can be traced back to the presence or absence of a nominal amount of certain chemicals. I wonder how the popular understanding of these processes will evolve as more and more is discovered and understood.

jugg1es 4y ago
This is like the right/left brain generalization that everyone seems to still believe in.
kemiller 4y ago
I think ADHD causes depression because you get constant negative feedback from (many) teachers & bosses.
- hirvi74 4y ago
  It's true, and I alluded to this more in depth in a comment in this chain. Growing up in the semi-rural South East, USA, where kids didn't get diagnosed with ADHD. (Fun fact -- I had 5 boys who were my childhood friends that grew up with. We all lived within 3 miles of each other, and all of us have ADHD -- something in the water maybe?) I didn't know I had ADHD until I was in a dark dark place in my early 20s after 4 years of college (only took me 6 years lol). I swear I have some kind of CPTSD from growing up with it. I developed all kinds of healthy and unhealthy coping mechanisms and a lot of anger and negative self-talk that I struggle with still to this day. I mean, I was chewed up and spit out by the public education system, little league sports, other children's parents, my peers, and even my own parents from time to time. Constantly, day in and day out, being punished, ridiculed, and humiliated for something I could not control. I didn't want to be that way, and I still don't want to be that way, but I am what I am. I would not consider myself to be anything but average intelligence, maybe even below average, but if it weren't for sheer luck and a determination to prove everyone wrong, then I do not think I would have survived.

harborseal 4y ago

Yes, but people are still being told by their psychiatrists that depression is caused by low serotonin levels as if it were an objective fact. Seeing this happen made me lose a lot of trust in the medical profession. Is it like this for all illnesses or just mental ones?

hirvi74 4y ago
I was told by a psychiatrist that I respect that one day in the future we may look back on psychiatry of today like we look at blood-letting and lobotomies of the past.
kerryoco 4y ago
many illnesses are reproducible. you can give people viruses and they do indeed get sick. so i don't think you need to discount the entirety of medicine. afaik, there is no reproducible causality for depression; we can't induce it. we only measure it's correlations and have % confidence in hypotheses.
kmmlng 4y ago
I don't think it is an isolated incident. Once something has become "known" among the public and the medical profession, it seems quite difficult to update it. Another example is the dietary cholesterol issue. The human body is incredibly complex and we have quite limited tools to study it, so we are bound to arrive at wrong conclusions. That by itself is to be expected, but what does really worry me is this missing knowledge updating mechanism. It can take decades for quite a substantial update on what we thought we knew to trickle down from academia to practicing medical professionals. At this point, if you have any kind of scientific literacy, it might be a good idea to verify whatever your doctor claims.
- alsetmusic 4y ago
  > It can take decades for quite a substantial update on what we thought we knew to trickle down from academia to practicing medical professionals. A recent ep of the Trickle Down podcast (premium offshoot of a show that studies conspiratorial thinking, Q Anon Anonymous), discussed how we learned to treat ulcers with antibiotics and then lost that information for something like fifty years. Changing the scientific understanding of their cause had a Greek doctor going to his country’s health ministry over and over and getting rejected despite results. I think you nailed it.

lighttower 4y ago

Can you point us to a source for the accepted real physiological effects of ADs that you shared above?

nth_order 4y ago
Sure - I should have given some sources in my original comment. The order of my list of purported mechanisms is also not really ordered by significance. I think generally, more and more mechanisms of AD efficacy are discovered, and it can seem that the more we know, the less we know. Additionally of course, there are like 15 different classes of ADs, with hundreds of different compounds in total. What we know for sure I think is that the serotonin and also the monoamine hypotheses of depression are highly oversimplified and even internally contradictory, and many more targets and way more general biochemical mechanisms in the brain must be involved in depression. But anyways, here are some pointers: - Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277931/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277931/) - Wikipedia: Biology of Depression (https://en.wikipedia.org/wiki/Biology_of_depression#Monoamines https://en.wikipedia.org/wiki/Biology_of_depression#Monoamin...) has some good sources - One source covering the 5-HT1A autoreceptor downregulation part in particular there is "Serotonin autoreceptor function and antidepressant drug action" (https://pubmed.ncbi.nlm.nih.gov/10890313/ https://pubmed.ncbi.nlm.nih.gov/10890313/) - This is also covered in "Mechanisms underlying the speed of onset of antidepressant response": https://link.springer.com/chapter/10.1007/978-3-0348-8344-3_4 https://link.springer.com/chapter/10.1007/978-3-0348-8344-3_... - I personally like the books "Antidepressants" by Leonard (that the previous paper is a chapter of) and "Anxiolytics" by Briley and Nutt. These discuss really a wealth of observed/purported mechanisms, also for example including the significance of late gene products. - Wikipedia: Pharmacology of antidepressants (https://en.wikipedia.org/wiki/Pharmacology_of_antidepressants https://en.wikipedia.org/wiki/Pharmacology_of_antidepressant...) has great sources, especially on the anti-inflammatory and immunomodulative pathways, and introducing HPA axis modulation as another possible pathway. - Here's something about the significance of common ADs being FIASMAs: https://www.semanticscholar.org/paper/High-activity-of-acid-sphingomyelinase-in-major-Kornhuber-Medlin/30ad3dc9ba2c57ba2648e8613bdcc1111bc8a85a https://www.semanticscholar.org/paper/High-activity-of-acid-... - also check out the related articles below for more interesting material. - ADs and neuroplasticity: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025168/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025168/ - ADs and neurogenesis (this is not clear-cut in its clinical significance, and many ordinary things like exercise can promote neurogenesis): https://www.sciencedirect.com/science/article/abs/pii/S0163725820300437 https://www.sciencedirect.com/science/article/abs/pii/S01637... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155214/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155214/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230505/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230505/

barbs 4y ago

How common is seretonin syndrome amongst people who take SSRIs? My understanding of seretonin syndrome is that it's a serious life-threatening condition that can occasionally occur when people take too much MDMA.